Protein tyrosine kinase (PTK) is a type of enzyme which plays an important role in normal cell growth. Protein tyrosine kinases catalyze the transfer of phosphate groups from ATP to the residues of the protein substrate. Many epidermal growth factor receptors (EGFR) have the effect of PTK, and the interaction of these receptors and growth factors is necessary in normal cell growth regulation. However, the overexpression of EGFR may cause excessive cell proliferation by the tyrosine kinase action of its own, and finally lead to the formation of tumors.
The epidermal growth factor receptor family can be divided into EGFR (Erb-BI), Erb-B2 (HER-2/neu), Erb-B3 and Erb-B4 according to structure. All of these epidermal growth factor receptors have been already confirmed to be related to most cancers.
Due to the important effect of the abnormal receptor kinases on the pathogenesis of cancer, the recent researches on anti-cancer agents focus on the development of the specific PTK inhibitors as potential anti-cancer therapeutic agents. The research of quinazoline derivatives as PTK inhibitors for further application to cancer treatment arouses wide attraction.
WO 96/30347 (Chinese patent application CN 96102992) and WO 96/33980 relate to some 4-(substituted-phenylamino)-quinazoline derivatives, their prodrugs, their pharmaceutically acceptable salts and their use in treating diseases caused by excessive cell proliferation.
WO 99/06378, WO 2000/31048 and WO 2000/06555 (Chinese patent application CN 99808949) also relate to substituted quinazoline derivatives having irreversible PTK inhibitory activity.
WO 2006/071017 mentions some quinazoline derivatives that inhibit growth of cancer cells.
WO 2007/082434 describes a novel type of 4-phenylamino quinazoline derivatives and their use as PTK inhibitors, wherein, it is proven by experiments that the compound N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide prepared in Example 8 possesses the relatively good effect of inhibiting the growth of human epidermoid squamous cancer cell A431 and human breast cancer cell BT-474. The compound also possesses the significant tumor-inhibiting effect on human epidermoid squamous cancer cell A431 implanted into a nude mouse. It is also proven by in vitro experiments that the compound has excellent inhibitory activity against Erb-B2 kinase.
A crystalline form has some influence on the physical properties of compounds. Because of different crystal lattice structures, pharmaceutical compounds with many kinds of crystalline forms may have not only different appearances (color and shape such as needle-shaped crystal, crystalline lamellar and crystalline granule), but also different physical properties (such as melting point, solubility, density, stability and hygroscopicity), resulting in that they show different dissolution and absorption behaviors in vivo, and this might have influence on the clinical effect and safety of the pharmaceutical compounds to a certain extent.
Specific crystalline form will have different thermodynamic behaviors as compared to amorphous state or another crystalline form. Melting point apparatus, thermogravimetric analysis (TGA) or Differential Scanning calorimetry (DSC) and the like can be used in laboratories to measure the thermal properties to differentiate a certain specific crystalline form, amorphous state and another crystalline form. Specific crystalline forms may have special spectral properties. For example, the data of both X-ray powder diffraction pattern and IR spectra can characterize specific crystalline forms.
The above-mentioned documents are hereby fully incorporated in this disclosure by reference herein.